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Neurocytomas are neuronal tumors that are usually intraventricular. Rare cases can arise from extraventricular sites. To our knowledge, only 29 cases of extraventricular neurocytoma of the sellar region (EVNSR) have been reported in the literature. We describe a case of a 39-year-old woman who presented with a one-month history of refractory headache, nausea and vomiting. Magnetic resonance imaging (MRI) showed a 5.1 × 3.1 × 2.2â cm sellar and suprasellar mass, suggestive of a pituitary adenoma (PA). She had hyponatremia, obstructive hydrocephalus, and panhypopituitarism at presentation (hypogonadism, adrenal insufficiency). After glucocorticoid replacement therapy and ventriculoperitoneal shunt, the vomiting and headache resolved, but she remained with nausea and hyponatremia. She was submitted to surgery, and histopathological analysis revealed a neurocytoma with positive immunostaining for arginine vasopressin. Syndrome of inappropriate antidiuresis (SIAD) was diagnosed but did not resolve after surgery due to residual tumor, despite fluid restriction and saline replacement. SIAD later resolved with empagliflozin. In conclusion, EVNSR is extremely rare and can be misdiagnosed as PA on MRI. In the context of SIAD and extraventricular neurocytoma, a secreting arginine vasopressin tumor must be considered. SIAD can be challenging to treat, with excision of the EVNSR the treatment choice and, alternatively, empagliflozin associated with fluid restriction.
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Somatic alpha thalassemia/mental retardation syndrome X-linked (ATRX) pathogenic variants have been shown to predict a malignant phenotype in neuroendocrine tumors. They were recently identified in aggressive pituitary tumors and carcinomas, mainly of corticotrophic origin. To our knowledge, these tumors are rare in a general cohort of pituitary tumors, with no cases described in null cell tumors. These variants can lead to loss of protein expression as revealed by immunohistochemistry. We describe a case of an aggressive null cell pituitary tumor with loss of ATRX expression. The patient underwent two transsphenoidal surgeries and radiotherapy and exhibited tumor growth despite conventional therapy. Analysis of the tumor samples revealed loss of ATRX expression in both surgical specimens, suggesting that ATRX may be a useful biomarker for the early identification of aggressive pituitary tumors.
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CONTEXT: Paltusotine is a nonpeptide selective somatostatin receptor 2 agonist in development as once-daily oral treatment for acromegaly. OBJECTIVE: To evaluate the efficacy and safety of paltusotine in the treatment of patients with acromegaly previously controlled with injected somatostatin receptor ligands (SRLs). METHODS: This phase 3, randomized, double-blind, placebo-controlled trial enrolled adults with acromegaly who had insulin-like growth factor I (IGF-I) ≤1.0 times the upper limit of normal (×ULN) while receiving a stable dose of depot octreotide or lanreotide. Patients were switched from injected SRLs and randomized to receive paltusotine or placebo orally for 36 weeks. The primary endpoint was proportion of patients maintaining IGF-I ≤1.0×ULN. Secondary endpoints were change in IGF-I level, change in Acromegaly Symptom Diary (ASD) score, and maintenance of mean 5-sample growth hormone (GH) <1.0 ng/mL. RESULTS: The primary endpoint was met: 83.3% (25/30) of patients receiving paltusotine and 3.6% (1/28) receiving placebo maintained IGF-I ≤1.0×ULN (odds ratio: 126.53; 95% CI: 13.73, >999.99; P<.0001). Paltusotine was also superior to placebo for all secondary endpoints: mean (±SE) change in IGF-I of 0.04±0.09×ULN versus 0.83±0.1×ULN (P<.0001); mean (±SE) change in ASD score of -0.6±1.5 versus 4.6±1.6 (P=.02); mean GH maintained at <1.0 ng/mL in 20/23 (87.0%) versus 5/18 (27.8%) patients (odds ratio: 16.61; 95% CI: 2.86, 181.36; P=.0003). The most common adverse events were acromegaly symptoms and gastrointestinal effects characteristic of SRLs. CONCLUSION: Replacement of injected SRLs by once-daily oral paltusotine was effective in maintaining both biochemical and symptom control in patients with acromegaly and was well tolerated.
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Injectable first-generation somatostatin receptor ligands (fg-SRLs) are the standard of care of medical treatment for acromegaly. While fg-SRLs control acromegaly in up to 50 % of patients, they may lead to bothersome injection pain and site reactions. Paltusotine is an investigational, highly selective somatostatin receptor subtype 2 agonist, which is administered orally once a day. To date, phase 2 and 3 clinical trials suggest paltusotine treatment can achieve biochemical and symptom control in acromegaly, with a safety profile comparable to those of the fg-SRLs. Since paltusotine is a once-daily oral drug, it may represent a future treatment option for addressing patient preference or improving quality of life.
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Acromegalia , Receptores de Somatostatina , Humanos , Receptores de Somatostatina/agonistas , Acromegalia/tratamiento farmacológicoRESUMEN
Partial or complete deficiency of anterior or posterior pituitary hormone production leads to central hypoadrenalism, central hypothyroidism, hypogonadotropic hypogonadism, growth hormone deficiency, or arginine vasopressin deficiency depending on the hormones affected. Hypopituitarism is rare and likely to be underdiagnosed, with an unknown but rising incidence and prevalence. The most common cause is compressive growth or ablation of a pituitary or hypothalamic mass. Less common causes include genetic mutations, hypophysitis (especially in the context of cancer immunotherapy), infiltrative and infectious disease, and traumatic brain injury. Clinical features vary with timing of onset, cause, and number of pituitary axes disrupted. Diagnosis requires measurement of basal circulating hormone concentrations and confirmatory hormone stimulation testing as needed. Treatment is aimed at replacement of deficient hormones. Increased mortality might persist despite treatment, particularly in younger patients, females, and those with arginine vasopressin deficiency. Patients with complex diagnoses, pregnant patients, and adolescent pituitary-deficient patients transitioning to adulthood should ideally be managed at a pituitary tumour centre of excellence.
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Hipopituitarismo , Humanos , Hipopituitarismo/diagnóstico , Hipopituitarismo/etiología , Hipopituitarismo/epidemiología , Femenino , MasculinoRESUMEN
Context: Patients with acromegaly are characterized by chronic exposure to high growth hormone (GH) and insulin-like growth factor-1 levels, known for their anabolic effect on skeletal muscle. Therefore, an increased skeletal muscle mass could be hypothesized in these individuals. Herein, we have performed a systematic revision of published evidence regarding skeletal muscle mass, quality, and performance in patients with acromegaly. Evidence Acquisition: A systematic review of the literature in the PubMed database up to September 1, 2023, was conducted with the following query: acromegaly AND ("muscle mass" OR "skeletal muscle"). We excluded studies that did not compare different disease states or used nonradiological methods for the skeletal muscle analyses, except for bioelectrical impedance analysis. Evidence Synthesis: Fifteen studies met the inclusion criteria. A total of 360 patients were evaluated for skeletal muscle mass, 122 for muscle fatty atrophy, and 192 for muscle performance. No clear evidence of increased skeletal muscle mass in patients with active disease compared to control or healthy individuals emerged. As for skeletal muscle quality, we observed a trend toward higher fatty infiltration among patients with acromegaly compared to healthy participants. Likewise, patients with active disease showed consistently worse physical performance compared to control or healthy individuals. Conclusion: Skeletal muscle in acromegaly has lower quality and performance compared to that of healthy individuals. The small number of published studies and multiple confounding factors (eg, use of different radiological techniques) contributed to mixed results, especially regarding skeletal muscle mass. Well-designed prospective studies are needed to investigate skeletal muscle mass in patients with acromegaly.
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No comprehensive classification system that guides prognosis and therapy of pituitary adenomas exists. The 2022 WHO histopathology-based classification system can only be applied to lesions that are resected, which represent few clinically significant pituitary adenomas. Many factors independent of histopathology provide mechanistic insight into causation and influence prognosis and treatment of pituitary adenomas. We propose a new approach to guide prognosis and therapy of pituitary adenomas by integrating clinical, genetic, biochemical, radiological, pathological, and molecular information for all adenomas arising from anterior pituitary cell lineages. The system uses an evidence-based scoring of risk factors to yield a cumulative score that reflects disease severity and can be used at the bedside to guide pituitary adenoma management. Once validated in prospective studies, this simple manageable classification system could provide a standardised platform for assessing disease severity, prognosis, and effects of therapy on pituitary adenomas.
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Adenoma , Neoplasias Hipofisarias , Humanos , Neoplasias Hipofisarias/diagnóstico , Neoplasias Hipofisarias/terapia , Estudios Prospectivos , Pronóstico , Adenoma/diagnóstico , Adenoma/terapia , Factores de RiesgoRESUMEN
PURPOSE: To prospectively evaluate the usefulness of T1-weighted imaging (T1WI) and diffusion-weighted imaging (DWI) sequences in predicting the consistency of macroadenomas. In addition, to determine their values ââas prognostic factors of surgical outcomes. METHODS: Patients with pituitary macroadenoma and surgical indication were included. All patients underwent pre-surgical magnetic resonance imaging (MRI) that included the sequences T1WI before and after contrast administration and DWI with the apparent diffusion coefficient (ADC) map. Post-surgical MRI was performed at least 3 months after surgery. The consistency of the macroadenomas was evaluated at surgery, and they were grouped into soft and intermediate/hard adenomas. Mean ADC values, signal on T1WI and the ratio of tumor ADC values ââto pons (ADCR) were compared with tumor consistency and grade of surgical resection. RESULTS: A total of 80 patients were included. A softened consistency was found at surgery in 53 patients and hardened in 27 patients. The median ADC in the soft consistency group was 0.532 × 10-3 mm2/sec (0.306 - 1.096 × 10-3 mm2/sec), and in the intermediate/hard consistency group was 0.509 × 10-3 mm2/sec (0.308 - 0.818 × 10-3 mm2/sec). There was no significant difference between the median values ââof ADC, ADCR and signal on T1W between the soft and hard tumor groups, or between patients with and without tumor residue. CONCLUSION: Our results did not show usefulness of the DWI and T1WI for assessing the consistency of pituitary macroadenomas, nor as a predictor of the degree of surgical resection.
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Adenoma , Neoplasias Hipofisarias , Humanos , Neoplasias Hipofisarias/diagnóstico por imagen , Neoplasias Hipofisarias/cirugía , Neoplasias Hipofisarias/patología , Imagen de Difusión por Resonancia Magnética/métodos , Imagen por Resonancia Magnética/métodos , Adenoma/diagnóstico por imagen , Adenoma/cirugía , Adenoma/patología , Estudios RetrospectivosRESUMEN
INTRODUCTION: Studies addressing the methylation pattern in adamantinomatous craniopharyngioma (ACP) are lacking. OBJECTIVE: To identify methylation signatures in ACPs regarding clinical presentation and outcome. METHODS: Clinical and pathology data were collected from 35 ACP patients (54% male; 18.1 years [2-68]). CTNNB1 mutations and methylation profile (MethylationEPIC/Array-Illumina) were analyzed in tumoral DNA. Unsupervised machine learning analysis of this comprehensive methylome sample was achieved using hierarchical clustering and multi-dimensional scaling. Statistical associations between clusters and clinical features were achieved using Fisher's test and global biological process interpretations were aided by Gene Ontology enrichment analyses. RESULTS: Two clusters were revealed consistently by all unsupervised methods (ACP-1: n = 18; ACP-2: n = 17) with strong bootstrap statistical support. ACP-2 was enriched by CTNNB1 mutations (100% vs 56%, P = 0.0006), hypomethylated in CpG Island (CGI), non-CGI sites, and globally (P < 0.001), and associated with greater tumor size (24.1 vs 9.5cm3, P = 0.04). Enrichment analysis highlighted pathways on signaling transduction, transmembrane receptor, development of anatomical structures, cell-adhesion, cytoskeleton organization, and cytokine binding, and also cell-type specific biological processes as regulation of oligodendrocytes, keratinocyte, and epithelial cells differentiation. CONCLUSION: Two clusters of ACP patients were consistently revealed by unsupervised machine learning methods, being one of them significantly hypomethylated, enriched by CTNNB1 mutated ACPs, and associated with increased tumor size. Enrichment analysis reinforced pathways involved in tumor proliferation and in cell-specific tumoral microenvironment.
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Acromegaly treatment has greatly evolved in recent decades, but there are still patients whose acromegaly is not controlled with currently available treatments, and there is a need to improve the treatment burden. Fortunately, there are new treatments under development that may increase treatment efficacy and convenience.
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Acromegalia , Humanos , Acromegalia/etiología , Acromegalia/terapia , Octreótido , Somatostatina/uso terapéutico , Péptidos Cíclicos , Factor I del Crecimiento Similar a la InsulinaRESUMEN
INTRODUCTION: Medical treatment of acromegaly is based in a `trial and error` approach. First-generation somatostatin receptor ligands (fg-SRL) are prescribed as first-line medical therapy to the vast majority of patients, despite lack of disease control in approximately 60% of patients. However, other drugs used in acromegaly treatment are available (cabergoline, pasireotide and pegvisomant). AREAS COVERED: In this article, we review and discuss the biomarkers of response to medical treatment in acromegaly. EXPERT OPINION: Biomarkers for fg-SRL that can already be applied in clinical practice are: gender, age, pretreatment GH and IGF-I levels, cytokeratin granulation pattern, and the expression of somatostatin receptor type 2. Using biomarkers of response could guide treatment towards precision medicine with greater efficacy and lower costs.
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Acromegalia , Humanos , Acromegalia/tratamiento farmacológico , Acromegalia/metabolismo , BiomarcadoresRESUMEN
Endogenous Cushing's syndrome results from excess glucocorticoid secretion, which leads to a myriad of clinical manifestations, comorbidities, and increased mortality despite treatment. Molecular mechanisms and genetic alterations associated with different causes of Cushing's syndrome have been described in the last decade. Imaging modalities and biochemical testing have evolved; however, both the diagnosis and management of Cushing's syndrome remain challenging. Surgery is the preferred treatment for all causes, but medical therapy has markedly advanced, with new drug options becoming available. Nevertheless, several comorbidities remain even after patient remission, which can affect quality of life. Accurate and timely diagnosis and treatment are essential for mitigating chronic complications of excess glucocorticoids and improving patient quality of life. In this Seminar, we aim to update several important aspects of diagnosis, complications, and treatment of endogenous Cushing's syndrome of all causes.
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Síndrome de Cushing , Humanos , Síndrome de Cushing/diagnóstico , Síndrome de Cushing/terapia , Calidad de Vida , Glucocorticoides/uso terapéuticoRESUMEN
This Consensus Statement from an international, multidisciplinary workshop sponsored by the Pituitary Society offers evidence-based graded consensus recommendations and key summary points for clinical practice on the diagnosis and management of prolactinomas. Epidemiology and pathogenesis, clinical presentation of disordered pituitary hormone secretion, assessment of hyperprolactinaemia and biochemical evaluation, optimal use of imaging strategies and disease-related complications are addressed. In-depth discussions present the latest evidence on treatment of prolactinoma, including efficacy, adverse effects and options for withdrawal of dopamine agonist therapy, as well as indications for surgery, preoperative medical therapy and radiation therapy. Management of prolactinoma in special situations is discussed, including cystic lesions, mixed growth hormone-secreting and prolactin-secreting adenomas and giant and aggressive prolactinomas. Furthermore, considerations for pregnancy and fertility are outlined, as well as management of prolactinomas in children and adolescents, patients with an underlying psychiatric disorder, postmenopausal women, transgender individuals and patients with chronic kidney disease. The workshop concluded that, although treatment resistance is rare, there is a need for additional therapeutic options to address clinical challenges in treating these patients and a need to facilitate international registries to enable risk stratification and optimization of therapeutic strategies.
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Hiperprolactinemia , Neoplasias Hipofisarias , Prolactinoma , Embarazo , Adolescente , Niño , Humanos , Femenino , Prolactinoma/terapia , Prolactinoma/tratamiento farmacológico , Neoplasias Hipofisarias/diagnóstico , Neoplasias Hipofisarias/terapia , Neoplasias Hipofisarias/complicaciones , Agonistas de Dopamina/uso terapéutico , Diagnóstico por Imagen , ProlactinaRESUMEN
Objective: To evaluate the long-term efficacy and safety of osilodrostat in patients with Cushing's disease. Methods: The multicenter, 48-week, Phase III LINC 4 clinical trial had an optional extension period that was initially intended to continue to week 96. Patients could continue in the extension until a managed-access program or alternative treatment became available locally, or until a protocol amendment was approved at their site that specified that patients should come for an end-of-treatment visit within 4 weeks or by week 96, whichever occurred first. Study outcomes assessed in the extension included: mean urinary free cortisol (mUFC) response rates; changes in mUFC, serum cortisol and late-night salivary cortisol (LNSC); changes in cardiovascular and metabolic-related parameters; blood pressure, waist circumference and weight; changes in physical manifestations of Cushing's disease; changes in patient-reported outcomes for health-related quality of life; changes in tumor volume; and adverse events. Results were analyzed descriptively; no formal statistical testing was performed. Results: Of 60 patients who entered, 53 completed the extension, with 29 patients receiving osilodrostat for more than 96 weeks (median osilodrostat duration: 87.1 weeks). The proportion of patients with normalized mUFC observed in the core period was maintained throughout the extension. At their end-of-trial visit, 72.4% of patients had achieved normal mUFC. Substantial reductions in serum cortisol and LNSC were also observed. Improvements in most cardiovascular and metabolic-related parameters, as well as physical manifestations of Cushing's disease, observed in the core period were maintained or continued to improve in the extension. Osilodrostat was generally well tolerated; the safety profile was consistent with previous reports. Conclusion: Osilodrostat provided long-term control of cortisol secretion that was associated with sustained improvements in clinical signs and physical manifestations of hypercortisolism. Osilodrostat is an effective long-term treatment for patients with Cushing's disease. Clinical trial registration: ClinicalTrials.gov, identifier NCT02180217.
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Hiperfunción de las Glándulas Suprarrenales , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT) , Humanos , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/tratamiento farmacológico , Hidrocortisona , Calidad de VidaRESUMEN
In the 2022 fifth edition of the WHO Classification of Endocrine Tumours and of Central Nervous System Tumours, pituitary adenomas are reclassified as neuroendocrine tumours (NETs). This change confers an oncology label to neoplasms that are overwhelmingly benign. A comprehensive clinical classification schema is required to guide prognosis, therapy and outcomes for all patients with pituitary adenomas. Pituitary adenomas and NETs exhibit some morphological and ultrastructural similarities. However, unlike NETs, pituitary adenomas are highly prevalent, yet indolent and rarely become malignant. This Perspective presents the outcomes of an interdisciplinary international workshop that addressed the merit and clinical implications of the classification change of pituitary adenoma to NET. Many non-histological factors provide mechanistic insight and influence the prognosis and treatment of pituitary adenoma. We recommend the development of a comprehensive classification that integrates clinical, genetic, biochemical, radiological, pathological and molecular information for all anterior pituitary neoplasms.
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Pasireotide long-acting release is effective in achieving biochemical control and reducing tumour volume in patients with acromegaly inadequately controlled by first-line therapy. As part of a long-term, real-world study at our centre, 20 of 50 patients receiving pasireotide benefited from a reduction in pasireotide dose. Pasireotide reduced insulin-like growth factor I (IGF-I) levels to below the upper limit of the normal range, with some patients responding within 1-3 months of treatment (n=11) and others after ≥4 months (n=9). Following pasireotide dose reduction, IGF-I levels showed a mild increase but remained within the normal range after a median of 39 months in the early responders and 17 months in the late responders. Glucose and glycated haemoglobin levels decreased following dose reduction. Identifying patients who may benefit from a reduction in pasireotide dose warrants further research as it may improve the management of pasireotide-associated hyperglycaemia in susceptible patients.
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Somatotroph adenomas are usually controlled with standard therapy, which can include surgery, medical treatment and radiotherapy. Some tumors have a more aggressive behavior and are refractory to standard therapy. In this review, we summarize the phenotype of these tumors and the current options for their management.